MOLECULAR EPIDEMIOLOGY OF HIV-ASSOCIATED CANCERS

Release Date:  April 6, 2000

PA NUMBER:  PA-00-086

National Cancer Institute
National Institute of Dental and Craniofacial Research

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.	

This Program Announcement (PA) replaces PA-97-057, which was published in NIH 
Guide Volume 26, Number 13, April 25, 1997.
 
PURPOSE

The Division of Cancer Control and Population Sciences of the National Cancer 
Institute (NCI) and the National Institute of Dental and Craniofacial 
Research (NIDCR) invite grant applications for interdisciplinary studies to 
better understand the molecular epidemiology and role of cofactors in the 
etiology of pre-neoplastic conditions and cancers occurring among persons 
infected with the human immunodeficiency virus (HIV), specifically those 
cancers associated with the DNA viruses, including human papilloma virus 
(HPV), Epstein Barr virus (EBV), and human herpes virus 8/Kaposi’s sarcoma 
associated herpes virus (HHV8/KSHV).  Cofactors of keen interest to the NCI  
include host genetic susceptibility and phenotype, age at first acquisition 
of the oncogenic virus, temporal association of acquisition of the oncogenic 
virus relative to time of HIV acquisition, effect of circulating viral load 
of the oncogenic virus, measurements of immune response, and role of 
behavioral factors such as tobacco use and diet.  It is expected that 
enhanced understanding of the molecular epidemiology of these tumors within 
the context of HIV-induced host immunodeficiency will yield information 
important to cancer control and prevention, including development of 
prophylactic vaccines, chemotherapeutic treatment modalities, other 
biomedical, and behavioral preventive interventions.  The NIDCR is 
principally interested in applying molecular epidemiology and the role of co-
factors in the etiology of perineoplastic lesions these DNA viruses cause in 
the oral cavity of the immune compromised host. These lesions usually occur 
in the oral cavity, early in acute HIV infection and are reestablished when 
immune incompetency is a fact.

This PA will expire in two years from the first receipt date.  NIH Grants 
policies apply to these awards.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas.  This PA, Molecular 
Epidemiology of HIV-Associated Cancers, is related to the priority areas of 
cancer and HIV infection.  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State or local governments, and eligible 
agencies of the Federal government. The total requested project period for an 
application submitted in response to the PA may not exceed five years. 
Foreign applications will receive no support for indirect costs.  Domestic 
applications may include international components but these components will 
receive no support for indirect costs.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project 
grant (R01) and competing supplements to existing NCI and NIDCR funded (R01) 
grants.  Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant. In the case of 
competing supplements to existing grants, applicants will be required to 
obtain and attach to their applications a document indicating that the 
submission of their application has been approved by the Principal 
Investigator of the research project grant.  This will be especially 
important if the application will require access to biological specimens from 
a central repository or to existing databases. 

Competing supplements must not extend beyond the funding period of the parent 
grant, the parent grant must have at least one year remaining in its project 
period after award of the supplement.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES  

Background

Infection by the human retrovirus, HIV, is a major public health problem 
throughout the world, particularly in the developing world.  Retroviruses may 
be directly oncogenic, or may foster the development of human cancers 
indirectly through immune suppression and subsequent reactivation of 
previously latent human oncogenic viruses.  The young age at which most 
people in the world become infected with HIV coupled with time spent living 
in an immunodeficient state portends that retroviral-associated cancers will 
impose a greater impact of years of potential life lost and quality of life 
than other cancers. 

The NCI and NIDCR have had a continuing interest in the study of the 
molecular epidemiology of pre-neoplastic conditions and cancers occurring 
among HIV-infected persons.  Some cancers, notably those associated with 
oncogenic human DNA viruses of the lymphoreticular system (non-Hodgkin’s 
lymphoma, Hodgkin’s Disease), soft tissue (Kaposi’s sarcoma,) and epithelial 
tissues (anogenital dysplasias and cancers) are significantly increased in 
incidence, display an aggressive pattern of development and progression in 
HIV-infected individuals, and/or remain refractory to standard therapies. It 
is expected that enhanced understanding of the molecular epidemiology of 
these tumors within the context of HIV-induced host immunodeficiency will 
yield information important to cancer control and prevention, including 
development of prophylactic vaccines, chemotherapeutic treatment modalities, 
and other biomedical preventive interventions.

The cancers of interest in this PA are ones associated with concomitant 
infection with DNA viruses that frequently confer latency, such as  Epstein 
Barr virus (EBV), human herpes virus 8/Kaposi’s sarcoma associated herpes 
virus (HHV8/KSHV) and  human papilloma virus (HPV).  In each case, infection 
by the concomitant virus appears to be necessary for subsequent oncogenesis, 
but not sufficient to lead to cancer in every case.  Therefore, both 
endogenous and exogenous cofactors must play a significant role.  For this 
PA, cofactors of special interest include host genetic susceptibility and 
phenotype, age at first acquisition of the oncogenic virus, temporal 
association of acquisition of the oncogenic virus relative to time of HIV 
acquisition, effect of circulating viral load of the oncogenic virus, 
measurements of immune response, and role of behavioral factors such as 
tobacco use and diet. 

This PA seeks to encourage research on the molecular and social epidemiology 
of preneoplastic conditions among HIV infected persons throughout the world 
and comparative epidemiologic studies based in several geographic areas.  An 
interdisciplinary approach that links the expertise of basic scientists with 
that of epidemiologists, clinicians, and behavioral scientists in an 
etiologic study is strongly encouraged.  Investigations may be conducted in 
adults and/or children. The areas of research listed below are not intended 
to be all inclusive, but are designed to give the applicant some direction as 
to the types of research that the NCI is interested in stimulating.  The 
NIDCR is interested in the areas of research listed with special focus on 
oral viral sentinel lesions and how these may affect HIV progression to AIDS.

o The (treated) natural history of cancers and pre-neoplastic changes in 
situations where the temporality of observed events, including timing of 
first infection or reactivation of existing infection, may be addressed

o The interplay of route of acquisition of the DNA virus, particularly 
HHV8/KSHV, and other cofactors on the molecular epidemiology and natural 
history of oncogenesis

o The role of host genetic susceptibility on the molecular epidemiology of 
these tumors 

o The effect of the age of first acquisition of the oncogenic virus, 
particularly with regards to the temporal association with acquisition of HIV

o The relationships of levels of circulating viral load of the oncogenic 
virus and of HIV, and the effects on the natural history of both HIV disease 
and oncogenesis

o The temporal relationships of immune markers measured both qualitatively 
and quantitatively with other variables of interest in the epidemiology of 
these tumors

o The effect of past and current use of recreational drugs, including 
alcohol, on the epidemiology of these tumors

o The role of diet, nutrition, and dietary supplements, both before 
acquisition of the viruses and after the recognition of infection, on the 
epidemiology of these tumors

o The effect of past and current use of tobacco products on the epidemiology 
of these tumors, including the relationships among nicotine biomarkers, 
measures of immune function, and circulating viral load

o The role of psychosocial processes in infection and disease detection and  
progression

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS  

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and  
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).  

All investigators proposing research involving human subjects should follow 
the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research", which have been published in the Federal Register of 
March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and 
Contracts of March 18, 1994, Volume 23, Number 11, available on the web at 
the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html
  
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.  

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are clear and compelling reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.  

All investigators proposing research involving human subjects should read the 
 NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects  that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES  

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants, with the modifications noted below.  Applications 
kits are available at most institutional offices of sponsored research and 
may be obtained from the Division of Extramural Outreach and Information 
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, 
Bethesda, MD 20892-7910, telephone 301/710-0267, email: [email protected].  
For those applicants with internet access, the 398 kit may be found at: 
http://grants.nih.gov/grants/forms.htm

Applicants are strongly encouraged to call the program contacts listed in 
INQUIRIES below with any questions.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.) The total direct costs must be 
requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities 
and Administrative (F&A) costs] for the initial budget period.  Items 8a and 
8b should be completed indicating the Direct and Total Costs for the entire 
proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 
4 of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION -  Prepare a Modular Grant Budget Narrative 
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages). At the top of the page, enter the total direct costs requested for 
each year.  This is not a form page.

o  Under Personnel, list key project personnel, including their names, 
percent of effort, and roles on the project. No individual salary information 
should be provided. However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is domestic or foreign.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount. 
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual"s qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST -  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

The number and title of the PA must be typed on line 2 of the face page of 
the application and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
checklist, and five signed, exact, single-sided photocopies, in one package 
to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical 
merit by an appropriate scientific review group convened in accordance with 
the standard NIH peer review procedures. 

As part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed assigned a priority score, and receive a 
second level review by the appropriate national advisory board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered by the reviewers in assigning the 
overall score weighting them as appropriate for each application.  Note that 
the application does not need to be strong in all categories to be judged 
likely to have a major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.
  
Significance: Does this study address an important problem?  If the aims of 
the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?  

Approach: Are the conceptual framework, design, methods, and analyzes 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  

Innovation: Does the project employ novel concepts, approaches or method?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?  

Investigator: is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?  

Environment: Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support ?  

The initial review group will also examine: the adequacy of plans to include 
both genders and minorities and their subgroups, and children as appropriate 
for the scientific goals of the research and plans for the recruitment and 
retention of subjects, the provisions for the protection of human and animal 
subjects, and the safety of the research environment.

AWARD CRITERIA
 
Applications will compete for available funds with all other recommended 
applications.  The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review, availability of 
funds, and programmatic priority.

INQUIRIES
  
Inquiries concerning this PA are encouraged, particularly during the planning 
phase of the grant applications.  The opportunity to clarify any issues or 
questions from potential applicants is welcome.

Direct inquiries regarding overall programmatic issues to:
 
Dr. Sandra L. Melnick or Vaurice Starks
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 240, MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 402-9375
FAX: (301) 402-4279
Email: [email protected]

Direct inquiries regarding applications with a primary focus on behavioral 
science to:

Dr. Wendy Nelson
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 4064, MSC 7326
Bethesda, MD 20892-7326
Telephone: (301) 435-4590
FAX: (301) 435-7547
Email: [email protected]
 
Direct inquiries regarding application with a primary focus on oral health 
to:

Denise Anne Russo, Ph.D. 
Infectious Diseases and Immunity Branch
Division of Extramural Research,
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18B 
Bethesda, MD 20892-6402
Telephone: (301) 594-2617 
FAX: (301) 480-8318
Email: [email protected]

Direct inquiries regarding fiscal matters to:
 
Bill Wells
Grants Administration Branch 
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Blvd.
Bethesda, MD, 20892 
Tel: 301-496-8796  
Fax: 301-496-8601
Email: [email protected]

Mr. Kevin Crist
Grants Management Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-38B, MSC 6402
Bethesda, MD 20892-6402
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: [email protected]

AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic Assistance Nos. 
93.393, 93.856, and 93.121.  Awards are made under authorization Sections 301 
and 405 of the Public Health Service Act amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or a Health Systems Agency 
Review.  

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-use of all tobacco products. In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking 
in certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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